Cancer has been one of the major plagues of society. Cancer appears to be a result of genetic defects, aging, viral infections, exposure to mutagens, and may have other causative events. The uncontrolled proliferation of non-functional cells can lead to rapid death or lingering illness. For the most part, approaches have depended upon the high proliferation of neoplastic cells as the basis for the therapy. Thus, many of the compounds are concerned with inhibiting DNA replication or causing dysfunctional replication resulting in cell death. However, neoplastic cells are not the only cells which are undergoing rapid proliferation in the body. Of particular moment are blood cells which are continuously being turned over through a highly orchestrated process emanating from a unique stem cell, which is able to differentiate into all of the different cellular pathways of the hematopoietic system, as well as providing a source for other cells, such as osteoclasts. Inhibition of the hematopoietic system results in the individual's susceptibility to opportunistic diseases, as well as adverse symptoms associated with aspects of the hematopoietic system not immediately directed to the immune system. Other tissues which require continuous replenishing include cutaneous tissue, hair follicles, linings of major organ systems, etc. Therefore, controlling cancer by inhibiting cell proliferation is problematical due to its adverse side effects.
Despite the extremely sophisticated tools which have been developed to identify genes associated with a particular phenotype, as yet, markers specific for neoplastic cells remain very rare. Morre et al. (1991) Biochim. Biophys. Acta 1057, 140-156; and Bruno et al. (1992) Biochem. J. 284, 625-628 reported an NADH oxidase activity which in cancer cells was constitutively activated and no longer hormone responsive.
The NADH oxidase activity appears to be associated with the ability of cells to proliferate. Inhibition of the enzyme results in a slowing of the proliferation of neoplastic cells. Since there appears to be a difference in the activity between the NADH oxidase of normal and neoplastic cells, there is substantial interest in being able to identify compounds which may selectively inhibit the NADH oxidase associated with neoplasia.
The NADH oxidase of petroleum ether-extracted plasma membranes is inhibited by certain quinone inhibitors. Sun et al. (1992) Proc. Natl. Acad. Sci. USA 89, 11126-11130. The involvement of NADH oxidase in the control of cell proliferation is described by Morre and Crane (1990) in Oxidoreduction at the Plasma Membrane: Relation to Growth and Transport. I. Animals Eds. Crane, Morre and Low (CRC Press, Boca Raton, Fla.), pp. 67-84. The activity in transformed cells and tissues was distinguished from that of liver in that the growth factor- and hormone-responsiveness was lost in plasma membranes of liver tissues transformed with 2-acetylaminofluorene. Morre et al. (1991) Biochim. Biophys. Acta 1057, 140-156. The same loss of responsiveness was observed with transplanted rat hepatomas. Bruno et al. (1992) Biochem,. J. 284, 625-628.